The objective of this project is to investigate the action of anlogues of amino acids on a synaptic field of the brain with unique pharmacological properties. The synaptic field to be studied is the termination of perforant path axons from lateral entorhinal cortex on dendrites of granule cells of the dentate gyrus in the hippocampal formation. Recently, the Principal Investigator for this proposal demonstrated that a homologous series of phosphonate analogues of acidic amino acids inhibit transmission of this synaptic field in a pattern suggesting highly specific antagonism to L-glutamic acid, a putative transmitter for the pathway. The experimental approach will be to prepare the desired glutamate analogues by the methods of snythetic organic chemistry. These compounds will then be examined for both antagonist and for agonist activity on the synaptic field of the dentate gyrus. Both antagonist and agonist activity will be measured by techniques of extracellular recording. The proposed research may be significant for a wide range of disciplines. Knowledge of structural requirements for potent and specific antagonists to major excitatory pathways of the brain may provide the rationale for preparing inhibitors to these pathways in vivo. Such drugs may be useful for differentiating anatomically homogeneous pathways into pharmacologically distinct compounds, for experimental psychology and physiology, and ultimately for clinical applications such as control of seizures.